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During development, pseudostratified epithelia undergo large scale morphogenetic events associated with increased mechanical stress. Using a variety of genetic and imaging approaches, we uncover that in the mouse E6.5 epiblast, where apical tension is highest, ASPP2 safeguards tissue integrity. It achieves this by preventing the most apical daughter cells from delaminating apically following division events. In this context, ASPP2 maintains the integrity and organisation of the filamentous actin cytoskeleton at apical junctions. ASPP2 is also essential during gastrulation in the primitive streak, in somites and in the head fold region, suggesting that it is required across a wide range of pseudostratified epithelia during morphogenetic events that are accompanied by intense tissue remodelling. Finally, our study also suggests that the interaction between ASPP2 and PP1 is essential to the tumour suppressor function of ASPP2, which may be particularly relevant in the context of tissues that are subject to increased mechanical stress.

We exploit Donald Trump’s nonpolitical background and surprise election victory to identify the value of sudden presidential ties among S&P 500 firms. In our setting firms did not choose to become politically connected, so we identify treatment effects comparatively free of selection bias prevalent in this literature. Firms with presidential ties enjoyed greater abnormal returns around the 2016 election. Since Trump’s inauguration, connected firms had better performance, received more government contracts, and were less subject to unfavorable regulatory actions. We rule out a number of confounding factors, including industry designation, sensitivity to Republican platforms, campaign finance, and lobbying expenditures.

Wittgenstein’s philosophy involves a general anti-platonism about properties or standards of similarity. On his view, what it is for one thing to have the same property as another is not dictated by reality itself; it depends on our classificatory practices and the standards of similarity they embody. Wittgenstein’s anti-platonism plays an important role in the private language sections and in his discussion of the conceptual problem of other minds. In sharp contrast to Wittgenstein’s views stands the contemporary doctrine of natural properties, which holds that there is an objective hierarchy of naturalness amongst properties, a hierarchy that is completely independent of our concepts or practices. Some authors have appealed to the natural properties view to offer an explicitly anti-Wittgensteinian account of sensation concepts. The paper discusses these competing views of properties and sensation concepts. It is argued that, if our account of concepts of conscious states starts from a commitment to natural properties, we are bound to recognize that our actual classificatory practices also play a crucial role in determining which properties our concepts pick out. On the other hand, if we start from the anti-platonist position, we are bound to recognize that we also need a notion of sameness of property that extends beyond our limited capacity to recognize similarity or sameness of property. The correct view, it is concluded, must occupy a middle position between an extreme anti-realism about properties and an extreme version of the natural properties view. It is suggested that Wittgenstein’s own view does just that.

Many philosophers think that there are phenomenal concepts: distinctive ways of thinking of experiences or sensations that can be grasped only by those who know what it is like to have those experiences or sensations. What light does Wittgenstein’s philosophy throw on this idea? In the literature, phenomenal concepts are often deployed for explicitly anti- Wittgensteinian purposes. Brian Loar and Christopher Peacocke, for example, both appeal to phenomenal concepts in arguing, against Wittgenstein, that a person can derive, from her own case, a concept of pain that can be applied to other people.1 And David Papineau and Katalin Balog argue that the existence of phenomenal concepts is inconsistent with Wittgenstein’s arguments against a private sensation language.2 Against these and similar views, I shall argue for the unorthodox view that a Wittgensteinian approach to sensations and sensation language can accommodate a version of the idea that there are distinctive concepts of sensations that are available only to those who know what it is like to have those sensations. For those who are interested in Wittgenstein, that is an important corrective to much that has been thought about the nature of a Wittgensteinian approach to these matters. For those who are interested in phenomenal concepts, my discussion helps to identify exactly what the existence of such concepts does and does not involve.

Wittgenstein’s philosophy involves a general anti-platonism about properties or standards of similarity. On his view, what it is for one thing to have the same property as another is not dictated by reality itself; it depends on our classificatory practices and the standards of similarity they embody. Wittgenstein’s anti-platonism plays an important role in the private language sections and in his discussion of the conceptual problem of other minds. In sharp contrast to Wittgenstein’s views stands the contemporary doctrine of natural properties, which holds that there is an objective hierarchy of naturalness amongst properties, a hierarchy that is completely independent of our concepts or practices. Some authors have appealed to the natural properties view to offer an explicitly anti-Wittgensteinian account of sensation concepts. The paper discusses these competing views of properties and sensation concepts. It is argued that, if our account of concepts of conscious states starts from a commitment to natural properties, we are bound to recognize that our actual classificatory practices also play a crucial role in determining which properties our concepts pick out. On the other hand, if we start from the anti-platonist position, we are bound to recognize that we also need a notion of sameness of property that extends beyond our limited capacity to recognize similarity or sameness of property. The correct view, it is concluded, must occupy a middle position between an extreme anti-realism about properties and an extreme version of the natural properties view. It is suggested that Wittgenstein’s own view does just that.

Wittgenstein writes: ‘The question can be raised: Is a state that I recognize on the basis of someone’s utterances really the same as the state he does not recognize this way?’ (Wittgenstein, Last Writings on Philosophy of Psychology, 8-9). Donald Davidson raises the same question: ‘If the mental states of others are known only through their behavioural and other outward manifestations, while this is not true of our own mental states, why should we think our own mental states are anything like those of others?’ (Davidson, ‘Three Varieties of Knowledge’, 207). And Davidson criticizes ‘Wittgensteinian’ accounts of our mental terms and concepts for failing to address the question. It is argued that Davidson’s own account of the asymmetry between first-person and third-person ascriptions of mental predicates itself fails to explain all that Davidson seems to suggest. And it is argued, contrary to many interpretations of Wittgenstein, that the question whether mental terms are univocal in their first-person and third-person uses is from a Wittgensteinian point of view legitimate and non-trivial. It is to be answered by achieving a reflective understanding of our practice of ascribing mental properties to ourselves and others – rather than by reference to supposedly more basic metaphysical facts about the sameness or difference of the properties our terms pick out. This approach is explained and defended.

Assisted reproductive technology (ART) has resulted in more than 5 million births worldwide. However, mainstream ART techniques are not always successful for an estimated 30% of infertile patients in whom gametes are nonviable. Most patients would clearly prefer genetic parenthood, currently possible only via the use of donated gametes or, in future, via the clinical use of artificial gametes (AGs) incorporating parental DNA. Despite much recent progress in the derivation of AGs, significant obstacles remain. Although it is possible to create artificial cells exhibiting some of the molecular and physiological traits of human gametes, they do not yet exhibit the same level of functionality as their in vivo counterparts. Most current effort pays scant attention to confirmation of molecular integrity and clinical applicability of AGs. Here we discuss the various clinical parameters used to assess gamete and embryo viability and discuss markers of gamete function that may be used within future studies attempting to derive AGs. The use of AGs may prove controversial to some members of the general public, and, as such, there is significant need for an appropriate ethical and legal framework governing the clinical use of such cells. However, provided these issues can be successfully overcome, it is highly likely that AGs will represent powerful biological tools for reproductive science, a valuable training resource for embryologists and for potential use in the clinical treatment of human infertility.

Debate continues over which morphological parameter is most important in selecting blastocysts for transfer. We aimed to investigate which parameter more accurately predicts the occurrence of a live birth by designing a retrospective cohort study of 1084 fresh elective single blastocyst transfers. Primary outcome was live birth rate (LBR) and secondary outcomes were implantation, clinical pregnancy and early pregnancy loss rates. Blastocyst expansion and inner cell mass (ICM), but not trophoectoderm, were associated with LBR in the definitive multivariable regression analysis. When ICM grade dropped from A to C the likelihood of achieving a live birth was reduced by 55% (OR=0.45, 95% CI 0.26-0.79, p = 0.005). These results were similar for clinical pregnancy rates. Early pregnancy loss rates of embryos with ICM grade C were more than double (38.0%) compared to those of grades A (15.95%) and B (17.17%, p = 0.002). The transfer of an embryo with an optimal inner cell mass reduces early pregnancy loss and increases the likelihood of a live birth. We did not find any significant association between trophectoderm and LBR in the multivariable analysis in contrast with recent studies.

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T-0). The median age at diagnosis was 58 years, and time from diagnosis to T-0 was 3.3 years. Following T-0, 213 (74%) patients had a treatment recorded with one or more regimens (median = 1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0 in 94 patients (44%) including >= partial response in 69 (32%). The median overall survival and event-free survival from T-0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs. Leukemia (2012) 26, 149-157; doi:10.1038/leu.2011.196; published online 29 July 2011

Interactions between invasive species and native fauna afford a unique opportunity to examine interspecific encounters as they first occur, without the complications introduced by coevolution. In northern Australia, the continuing invasion of the highly toxic cane toad Bufo marinus poses a threat to many frog-eating predators. Can predators learn to distinguish the novel toxic prey item from native prey (and thus, avoid being poisoned), or are longer-term genetically based changes to attack behaviour needed before predators can coexist with toads? To predict the short-term impact of cane toads on native predators, we need to know the proportion of individuals that will attack toads, the proportion surviving the encounter, and whether surviving predators learn to avoid toads. We quantified these traits in a dasyurid (common planigale, Planigale maculata) that inhabits tropical floodplains across northern Australia. Although 90% of naïve planigales attacked cane toads, 83% of these animals survived because they either rejected the toad unharmed, or killed and consumed the prey snout-first (thereby avoiding the toxin-laden parotoid glands). Most planigales showed one-trial learning and subsequently refused to attack cane toads for long time periods (up to 28 days). Toad-exposed planigales also avoided native frogs for up to 9 days, thereby providing an immediate benefit to native anurans. However, the predators gradually learnt to use chemical cues to discriminate between frogs and toads. Collectively, our results suggest that generalist predators can learn to distinguish and avoid novel toxic prey very rapidly - and hence, that small dasyurid predators can rapidly adapt to the cane toad invasion. Indeed, it may be feasible to teach especially vulnerable predators to avoid cane toads before the toads invade, by deploying low-toxicity baits that stimulate taste-aversion learning. © 2008 The Authors.

Background: NHS-funded ART cycles are gradually being reduced or completely stopped by several Clinical Commissioning Groups (CCGs) aiming to make savings of between £300,000- £800,000 per year. This has led to a decrease in NHS ART treatment available, which may lead to an increasing number of UK residents seeking treatment overseas. Overseas ART treatment may be associated with a higher rate of multiple pregnancies, associated with higher morbidity for patients, and cost to the NHS. I proposed a study to assess if a One-stop fertility pathway could reduce investigation duration and lead to cost savings that could be used to maintain funding for ART cycles and improve the patients’ Quality of Life (QoL). I also reviewed the High Multiple Pregnancies (HMP) at the John Radcliffe (JR) Hospital in Oxford to assess the impact from ART performed in the UK and overseas. Methods: A prospective observational study comparing duration, costs and QoL of 191 participants going through the Conventional pathway and 28 participants going through a One-Stop pathway. And a retrospective observational review of 43 (HMP) at the JR over 7 years. Results: One-stop pathway reduced the average duration by 426.9 days p=0.016 and cost by £435.1 p= Conclusions: One-Stop Fertility clinics decrease the duration and cost of fertility investigation, saving as much as £670,415.28 per year for a CCG. These savings could be “ring-fenced” to fund NHS ART cycles which may lead to reductions in HMPs in the UK. The study recommends the establishment of a UK National Database for HMP and offering early psychological support, especially to female patients, whose QoL approaches levels observed in clinical depression.

Mammalian embryo hatching from the zona pellucida (ZP) is a prerequisite to undergo subsequent implantation, but little is known about the involved molecules and regulatory mechanisms underlying the hatching process. Hatching failure can lead to implantation failure. Clinical laboratories have developed the non-contact infra-red diode laser to manipulate ZP for various purpose, such as assist embryo hatching and facilitate embryo biopsy procedure. Previous studies attempted to investigate the safety and efficacy of laser-assisted ZP manipulations; however, there is a significant paucity of safety evidence at the molecular level and the efficacy remains controversial. This thesis aimed to investigate the effect of laser-assisted ZP manipulations on embryo competency and transcriptome, and to uncover the regulatory mechanisms underlying the hatching process. In chapter 3, I analysed 181 questionnaires to characterise the clinical application pattern of ZP manipulation and found that laser-assisted ZP manipulation is extensively used in clinics, especially prior to embryo biopsy (89.5%). However, a huge disparity existed with regards to the current clinical practice, and no standardisation is evident at present. In chapter 4, mouse embryos were used to investigate the safety of the three most commonly used laser-assisted ZP manipulations, including ZP drilling (n=349), ZP partial drilling (n=319), and ZP thinning (n=297). No overt deleterious effects were identified with regards to the blastocyst development, cell apoptosis, heat shock stress (HSP70), and the expression of key developmental genes. However, the results demonstrated that laser-assisted ZP drilling significantly advance the hatching rate (81.1% (210) vs 40.1% (111), P

This thesis is an evaluation of doxastic normativism. Doxastic normativism is the theory that belief is essentially normative, and that the norm of belief is a constitutive norm. After introducing the taxonomy of normativist views I use throughout the thesis, I discuss four versions of doxastic normativism: state normativism, conceptual normativism, intentional teleologism, and teleo-functionalism. The first two are those traditionally referred to as “doxastic normativism”, and they are the main targets of the thesis. Discussion of the second two is less extensive, and serves to show that the central problem for normativism lies not in the kind of normativity that it claims is essential to belief, but in the attempt to make any normative property whatsoever a necessary condition for belief. I develop undercutting objections to two arguments for state normativism and to one argument for conceptual normativism. My objections draw on i.a. the semantics of correctness ascriptions, the norms of other intentional states, the nature of rationality, and the evidential sensitivity of belief. Then there are several rebutting objections, drawing on non-agential mental states, the normative classification of epistemically deviant mental states, and difficulties for state-differentiation through norms. The discussions of teleologism and teleo-functionalism demonstrate that these views, although making much weaker claims about belief, fall prey as well to the main problems identified for the core normativist views. The thesis closes on a chapter offering reflections about the reasons behind the failures of normativism, as well as a descriptive theory of belief that I argue can fulfil the explanatory desiderata of doxastic normativism.

Borderline conscious creatures are neither definitely conscious nor definitely not conscious. In this thesis, I explain what borderline consciousness is and why it poses a significant epistemological challenge to scientists who investigate phenomenal consciousness as a natural kind. When these scientists discover more than one overlapping kind in their samples of conscious creatures, how can they identify the kind to which all and only conscious creatures belong? After assessing three pessimistic responses, I argue that different groups of scientists can legitimately use the concept of phenomenal consciousness to refer to different kinds, in accord with their empirical interests. They can thereby resolve three related impasses on the status of borderline conscious creatures, the neural structure of phenomenal consciousness, and the possibility of artificial consciousness. The thesis has three parts: First, I analyse the concept of borderline consciousness. My analysis counters several arguments which conclude that borderline consciousness is inconceivable. Then I explain how borderline consciousness produces the multiple kinds problem in consciousness science. Second, I assess three recent philosophical responses to this problem. One response urges scientists to eliminate the concept of consciousness, while another judges them to be irremediably ignorant of the nature of consciousness. The final response concludes that scientific progress is limited by the concept's referential indeterminacy. I argue that these responses are too pessimistic, though they point to a more promising approach. Third, I propose that empirically constrained stipulation can solve the multiple kinds problem. Biologists face the same problem because of their longstanding controversy over what counts as a species. Building on new arguments for stipulating the reference of species concepts, I demonstrate that this use of stipulation in biology is neither epistemologically complacent nor metaphysically capricious; it also need not sow semantic confusion. Then I defend its use in consciousness science. My approach is shown to be consistent with our understanding of natural kinds, borderline cases, and phenomenal consciousness.

In vitro fertilization treatments are responsible for 1-5% births in industrialized countries. The safest way to generate a pregnancy is to transfer a single embryo to the mother, reducing the likelihood of multiple gestations. Hence, in order to maximize the chance of success, it is extremely important that the embryo prioritised for transfer is the most capable within the cohort of embryos generated by the patient. Along with cytogenetic components, it has been suggested that embryo protein expression patterns may correlate with its ability to implant. However, embryo proteomics strategies have not been easy to harness mainly due to the complexity of the media the embryos are cultured in, and the low concentration of the proteins that are secreted. In this study, the use of the blastocentesis procedure, which allows the safe retrieval of embryo inner fluid (blastosol), was described. The use of the blasocoel fluid as a source of embryonic DNA for preimplantation genetic assessment was also investigated. From this highly purified embryonic sample, a comprehensive catalogue of proteins present in the human blastosol was generated using standard and custom- made mass spectrometry strategies. The embryonic origin of these proteins was validated by gene expression microarray and RNASeq analysis. These experiments also allowed the identification of differentially expressed genes in the first two cell lineages, the Inner Cell Mass and the Trophectoderm. Finally, a targeted proteomics strategy able to measure part of the previously described protein targets in single blastosol samples was employed. The correlation between the presence and abundance of proteins of interest in single blastosols and several biological characteristics of the embryo, including its chromosomal status, was assessed. These data are of major interest for the understanding of human embryo development. The validated embryo-derived protein catalogue and blastocyst gene expression profiles generated in this study, provides access to a thorough document for consultation in human embryology proteomics-based experiment design, paving the way to next-generation proteomic-based embryo assessment.

The first half of this thesis addressed the clinical question of whether the phenotype of peripheral immune cells is affected by the normal menstrual cycle and whether there are differences in women with recurrent unexplained miscarriage. In chapter 2, a mid-luteal type 1 shift was demonstrated in NKdim and cytotoxic T cells in the menstrual cycle. In addition, women with recurrent miscarriage had increased numbers of type 1 (IL-18R+) cytotoxic lymphocytes and an increased number of NKdim and NKbright cells in the mid-luteal phase of the cycle.The shift to type 2 immunity seen in normal pregnancy has been previously identified from the second half of the first trimester. In chapter 3 this type 2 shift was seen in NK and T cells as early as 9 days post implantation. ST2L (the ligand for IL-33 and a marker of type 2 cells) was consistently up regulated at this very early stage post implantation in women who were pregnant.The second half of this thesis investigated IL-33 and ST2 in normal and pathological pregnancy. In chapter 4 it was shown that circulating IL-33 did not change over the course of pregnancy but that sST2 (the soluble decoy receptor) increased significantly in the 3rd trimester of normal pregnancy. Both IL-33 and ST2 were variably expressed by the pre-implantation human blastocyst, as well as by the 1st and 3rd trimester placenta.Finally, chapter 5 showed a potential role for ST2 in pre-eclampsia, an inflammatory disease of pregnancy. sST2 was significantly elevated in the third trimester in women who went on to develop pre-eclampsia even prior to the onset of disease. Using an in vitro model of placental perfusion, it was shown that sST2 can be secreted by the placenta, suggesting that sST2 may play a significant role in pregnancies complicated by this disease.

Open ileal pouch surgery leads to high rates of adhesive small-bowel obstruction (SBO). A laparoscopic approach may reduce these complications. We aimed to review the incidence of adhesive SBO-related complications after open pouch surgery and to model the potential financial impact of a laparoscopic approach purely as an adhesion prevention strategy. We reviewed cases of open ileal pouch patients kept on a database and examined annually. Case notes were studied for episodes of adhesive SBO requiring admission or reoperation. Similar parameters were studied in a small series undergoing laparoscopic pouch surgery. The financial burden of the open access complications was estimated and potential financial impact of a laparoscopic approach modeled. Two hundred seventy-six patients were followed up after open surgery (median, 6.3; range, 0.2–20.1 years). There were 76 (28%) readmissions (median length of stay, 7.4 days) in 53 patients (19%) and 28 (10%) reoperations (43% within 1 year). Laparoscopic patients required less adhesiolysis at second-stage surgery (0% vs 36%, p